The dynamics of the viral decline immediately following the start of therapy for chronic hepatitis C virus (HCV) infection may have prognostic potential for ultimate sustained virologic response (SVR). Considerable inter-individual variability in the decline has been reported, including differences by race. The human major histocompatability complex (MHC) genes encode the human leukocyte antigens (HLA), which are important in the immune response to viral infections. We examined whether carriage of specific human MHC alleles are associated with the rate of the early viral decline. Longitudinal viral level data (baseline and days 1, 2, 7, 14 and 28 of treatment), medium resolution MHC genotyping, and random coefficients models were used to examine associations between MHC class I and class II allele carriage and the dynamics of the viral decline in 180 African Americans (AAs) and 194 Caucasian Americans (CAs) with genotype-1 HCV infection over the first 28 days of treatment with peginterferon-alfa-2a and ribavirin. Baseline viral levels were similar by race, irrespective of allele carriage. However, the rate of change in the viral decline was associated with both allele and race. Among the four subgroups defined by race and specific allele, fastest rates of decline were observed (in terms of estimated mean viral declines log10 IU/mL during the first four weeks) in CA non-carriers for A*03 (2.75;p=0.018), in CA carriers for Cw*03 (2.99;p=0.046), in CA non-carriers for DQA1*04 (2.66;p=0.018), and DQB1*0402 (2.65;p=0.018). MHC alleles are associated with the viral decline during the first 28 days of peginterferon therapy. Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-alfa-2a is successful in eradicating virus from only 30%-80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) (RR=0.80;95%C.I.: 0.66- 0.98;p=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79;95%C.I.: 0.66-0.94;p=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78;95%C.I.: 0.66-0.94;p=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78;95% C.I.: 0.62-1.0;p=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy. . Early and rapid viral decline during the first 28 days of treatment for chronic hepatitis C virus (HCV) with pegylated interferon and ribavirin therapy is an important predictor of sustained virologic response (SVR). Interferon stimulated genes (ISGs) play an important role in the antiviral response to HCV. This study examines whether ISG variants are associated with viral level decline during the first 28 days of treatment. The association between single nucleotide polymorphisms in 16 ISGs and the dynamics of viral decline was examined in 180 African American and 194 Caucasian American patients with genotype-1 HCV infection treated with pegylated interferon alpha-2a and ribavirin using linear mixed models. Viral levels were obtained prior to treatment and at days 1, 2, 7, 14 and 28. Analyses were conducted separately by race. Statistically significant (p<0.05) polymorphisms were observed in MX2, OASL, STAT1 and STAT2, but different patterns of decline were observed in the race groups. Similar viral level decline patterns were observed in both race groups for variants in IFNAR1, IRF1, MX1, OAS3 and PKR, but were not statistically significant. Genetic variants in some ISGs were associated with 28 day viral decline, but patterns of viral level decline differed by race. These results indicate that some ISG polymorphisms may play a role in the 28 day viral decline.